Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.08.002
Elsa Brunet-Ratnasingham , Tasha Tsao , Rashmi P. Mohanty , Octavio Arias-Soto , Bhavya Kapse , John R. Greenland , Daniel R. Calabrese
The pathophysiology of cystic fibrosis (CF) leads to epithelial cell hypoxia, which directly affects epithelial cells. CF is caused by genetic disruption of the CF transmembrane receptor that has important direct impacts on cell signaling and proteotoxic stress, and indirect impacts through microbiome alterations. How these alterations impact hypoxia signaling is not known. We collected primary human airway cells from explanted lungs of individuals with or without CF, differentiated them at air-liquid interface, and subjected them to short-term hypoxia. Differential gene expression was assessed by RNAseq, with findings validated by flow cytometry. We also assessed the impacts of modulator therapies on CF epithelial cells. While there was overlap in the transcriptomic response to hypoxia between CF and referent epithelial cells, CF cells activated additional pathways. In CF cells under hypoxia, activation of the hypoxia pathway was associated with HIF1α, EMT, and immune-related pathways, the latter not seen in referent cells. Among HIF1α related genes, VEGF was uniquely increased in cells from CF, and its expression was modulated through HIF1α signaling. We show that correction of CFTR blunts exaggerated response to hypoxia in CF cells. These results suggest CF airway cells have an exacerbated response to hypoxia, which may be alleviated through the correction of misfolded CFTR.
{"title":"Cystic fibrosis airway epithelial cells have an exaggerated response to hypoxia that is partially reversible through transmembrane receptor modulation","authors":"Elsa Brunet-Ratnasingham , Tasha Tsao , Rashmi P. Mohanty , Octavio Arias-Soto , Bhavya Kapse , John R. Greenland , Daniel R. Calabrese","doi":"10.1016/j.jcf.2025.08.002","DOIUrl":"10.1016/j.jcf.2025.08.002","url":null,"abstract":"<div><div>The pathophysiology of cystic fibrosis (CF) leads to epithelial cell hypoxia, which directly affects epithelial cells. CF is caused by genetic disruption of the CF transmembrane receptor that has important direct impacts on cell signaling and proteotoxic stress, and indirect impacts through microbiome alterations. How these alterations impact hypoxia signaling is not known. We collected primary human airway cells from explanted lungs of individuals with or without CF, differentiated them at air-liquid interface, and subjected them to short-term hypoxia. Differential gene expression was assessed by RNAseq, with findings validated by flow cytometry. We also assessed the impacts of modulator therapies on CF epithelial cells. While there was overlap in the transcriptomic response to hypoxia between CF and referent epithelial cells, CF cells activated additional pathways. In CF cells under hypoxia, activation of the hypoxia pathway was associated with HIF1α, EMT, and immune-related pathways, the latter not seen in referent cells. Among HIF1α related genes, VEGF was uniquely increased in cells from CF, and its expression was modulated through HIF1α signaling. We show that correction of CFTR blunts exaggerated response to hypoxia in CF cells. These results suggest CF airway cells have an exacerbated response to hypoxia, which may be alleviated through the correction of misfolded CFTR.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1156-1165"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.07.003
Jane E. Gross , Jason Fullmer , Gregory McClelland , Silvia M. Caceres , Katie R. Poch , Nabeeh A. Hasan , Fan Jia , L. Elaine Epperson , Ettie M. Lipner , Charmie K. Vang , Jennifer R. Honda , Matthew J. Strand , Vinicius Calado Nogueira de Moura , Charles L. Daley , Michael Strong , Jerry A. Nick
Background
Cystic Fibrosis (CF) Centers worldwide have reported healthcare-associated outbreaks of nontuberculous mycobacteria (NTM). We report a retrospective investigation of shared Mycobacterium abscessus strains among people with cystic fibrosis (pwCF) receiving care at Dell Children’s/Ascension combined Pediatric and Adult CF Program (DCMC).
Methods
Whole genome sequencing (WGS) was used to identify genetically similar isolates among 167 NTM isolates from 57 pwCF. Epidemiological investigation, respiratory and environmental isolate comparisons, and watershed mapping were performed.
Results
WGS analysis revealed four M. abscessus clusters, two ssp. abscessus and two ssp. massiliense. One subject was infected with two distinct clustered M. abscessus (ssp. abscessus and ssp. massiliense). Epidemiologic investigation demonstrated opportunities for healthcare-associated transmission within all clusters. Two ssp. massiliense subject pairs had healthcare overlaps and high genomic relatedness, including one cohabitating sibling pair. M. abscessus recovered from DCMC revealed genetic similarity to a respiratory isolate from one patient who was never exposed to the hospital environment.
Conclusions
We identified shared M. abscessus strains via genomic analysis among pwCF at DCMC. None of the clustered patient isolates matched hospital environmental isolates at the genomic level. One hospital environmental isolate had genomic similarity to a respiratory isolate of M. abscessus, but the epidemiologic investigation revealed no evidence of subject exposure to the hospital setting. One ssp. massiliense subject pair had the same level of pangenome relatedness as the sibling pair and epidemiological investigation revealed overlap in the clinic, supporting healthcare-associated person-to-person transmission among the pair within a cluster. One pwCF had polyclonal clustered infections, suggesting multiple environmental sources of acquisition outside the healthcare environment.
{"title":"Genomic and epidemiologic investigation of Mycobacterium abscessus isolates in a cystic fibrosis center to determine potential routes of transmission","authors":"Jane E. Gross , Jason Fullmer , Gregory McClelland , Silvia M. Caceres , Katie R. Poch , Nabeeh A. Hasan , Fan Jia , L. Elaine Epperson , Ettie M. Lipner , Charmie K. Vang , Jennifer R. Honda , Matthew J. Strand , Vinicius Calado Nogueira de Moura , Charles L. Daley , Michael Strong , Jerry A. Nick","doi":"10.1016/j.jcf.2025.07.003","DOIUrl":"10.1016/j.jcf.2025.07.003","url":null,"abstract":"<div><h3>Background</h3><div>Cystic Fibrosis (CF) Centers worldwide have reported healthcare-associated outbreaks of nontuberculous mycobacteria (NTM). We report a retrospective investigation of shared <em>Mycobacterium abscessus</em> strains among people with cystic fibrosis (pwCF) receiving care at Dell Children’s/Ascension combined Pediatric and Adult CF Program (DCMC).</div></div><div><h3>Methods</h3><div>Whole genome sequencing (WGS) was used to identify genetically similar isolates among 167 NTM isolates from 57 pwCF. Epidemiological investigation, respiratory and environmental isolate comparisons, and watershed mapping were performed.</div></div><div><h3>Results</h3><div>WGS analysis revealed four <em>M. abscessus</em> clusters, two ssp. <em>abscessus</em> and two ssp. <em>massiliense</em>. One subject was infected with two distinct clustered <em>M. abscessus</em> (ssp. <em>abscessus</em> and ssp. <em>massiliense</em>). Epidemiologic investigation demonstrated opportunities for healthcare-associated transmission within all clusters. Two ssp. <em>massiliense</em> subject pairs had healthcare overlaps and high genomic relatedness, including one cohabitating sibling pair. <em>M. abscessus</em> recovered from DCMC revealed genetic similarity to a respiratory isolate from one patient who was never exposed to the hospital environment.</div></div><div><h3>Conclusions</h3><div>We identified shared <em>M. abscessus</em> strains via genomic analysis among pwCF at DCMC. None of the clustered patient isolates matched hospital environmental isolates at the genomic level. One hospital environmental isolate had genomic similarity to a respiratory isolate of <em>M. abscessus</em>, but the epidemiologic investigation revealed no evidence of subject exposure to the hospital setting. One ssp. <em>massiliense</em> subject pair had the same level of pangenome relatedness as the sibling pair and epidemiological investigation revealed overlap in the clinic, supporting healthcare-associated person-to-person transmission among the pair within a cluster. One pwCF had polyclonal clustered infections, suggesting multiple environmental sources of acquisition outside the healthcare environment.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1114-1123"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.09.004
Laura Schembri , Delyth Jones , Siân Bentley , Siobhán Carr , Ian Balfour-Lynn
Background
Clinical trials showed improved faecal elastase (FE-1) levels in younger children with cystic fibrosis (cwCF) on elexacaftor/tezacaftor/ivacaftor (ETI). Lower sweat chloride has been linked to better clinical outcomes in people with CF. Our previous work showed increased vitamin A levels in cwCF aged 5–15 years. We aimed to evaluate changes in FE-1 and vitamin levels and explore associations between sweat chloride and FE-1, in 2–6-year-olds starting ETI in a real-world setting.
Methods
In a large UK paediatric specialist CF centre, cwCF newly eligible for ETI when UK licensing age decreased to 2 years were included. Baseline vitamin A, D, E and FE-1 levels were collected retrospectively. Post ETI, FE-1, vitamin and sweat chloride levels were collected prospectively.
Results
51/68 eligible patients were included. Median age on starting ETI was 4.1 (range 2.0–6.5) years. 12/43 (28 %) of pancreatic insufficient (PI) patients became pancreatic sufficient (PS) 6 months after ETI (p = 0.0005); 3 reverted to PI by 12 months, and 1 other patient became PS by 12 months. Enzymes were reduced or stopped for most children who became PS. Change in FE-1 negatively correlated with post ETI sweat chloride level (Spearman’s ρ -0.49, p = 0.007). There was a significant increase in median vitamin D levels (p = 0.007) but no significant changes in vitamins A or E; particularly, high vitamin A levels were not seen.
Conclusions
Reversal of PI appears possible in preschool cwCF, but may not be sustained. Enzyme adjustments should be made cautiously, and monitoring of symptoms and FE-1 continued.
{"title":"Real-world pancreatic function recovery and fluctuation in young children with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor","authors":"Laura Schembri , Delyth Jones , Siân Bentley , Siobhán Carr , Ian Balfour-Lynn","doi":"10.1016/j.jcf.2025.09.004","DOIUrl":"10.1016/j.jcf.2025.09.004","url":null,"abstract":"<div><h3>Background</h3><div>Clinical trials showed improved faecal elastase (FE-1) levels in younger children with cystic fibrosis (cwCF) on elexacaftor/tezacaftor/ivacaftor (ETI). Lower sweat chloride has been linked to better clinical outcomes in people with CF. Our previous work showed increased vitamin A levels in cwCF aged 5–15 years. We aimed to evaluate changes in FE-1 and vitamin levels and explore associations between sweat chloride and FE-1, in 2–6-year-olds starting ETI in a real-world setting.</div></div><div><h3>Methods</h3><div>In a large UK paediatric specialist CF centre, cwCF newly eligible for ETI when UK licensing age decreased to 2 years were included. Baseline vitamin A, D, E and FE-1 levels were collected retrospectively. Post ETI, FE-1, vitamin and sweat chloride levels were collected prospectively.</div></div><div><h3>Results</h3><div>51/68 eligible patients were included. Median age on starting ETI was 4.1 (range 2.0–6.5) years. 12/43 (28 %) of pancreatic insufficient (PI) patients became pancreatic sufficient (PS) 6 months after ETI (<em>p</em> = 0.0005); 3 reverted to PI by 12 months, and 1 other patient became PS by 12 months. Enzymes were reduced or stopped for most children who became PS. Change in FE-1 negatively correlated with post ETI sweat chloride level (Spearman’s ρ -0.49, <em>p</em> = 0.007). There was a significant increase in median vitamin D levels (<em>p</em> = 0.007) but no significant changes in vitamins A or E; particularly, high vitamin A levels were not seen.</div></div><div><h3>Conclusions</h3><div>Reversal of PI appears possible in preschool cwCF, but may not be sustained. Enzyme adjustments should be made cautiously, and monitoring of symptoms and FE-1 continued.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1094-1097"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.07.008
Meghana Sathe , Steven D. Freedman , Melissa S. Putman , Robert Gallotto , Marcie Clarkin , Danielle Gallotto , Kateryna Pierzynowska , Drucy Borowitz
Background
Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin.
Methods
This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively.
Results
ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (p = 0.03; p = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (p = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred.
Conclusions
ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.
{"title":"Results of a clinical trial of ANG003, a non-porcine pancreatic enzyme replacement therapy, in people with cystic fibrosis","authors":"Meghana Sathe , Steven D. Freedman , Melissa S. Putman , Robert Gallotto , Marcie Clarkin , Danielle Gallotto , Kateryna Pierzynowska , Drucy Borowitz","doi":"10.1016/j.jcf.2025.07.008","DOIUrl":"10.1016/j.jcf.2025.07.008","url":null,"abstract":"<div><h3>Background</h3><div>Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin.</div></div><div><h3>Methods</h3><div>This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively.</div></div><div><h3>Results</h3><div>ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (<em>p</em> = 0.03; <em>p</em> = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (<em>p</em> = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred.</div></div><div><h3>Conclusions</h3><div>ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1043-1050"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elexacaftor/tezacaftor/ivacaftor (ETI) therapy reduces airway infection rates with Pseudomonas aeruginosa (PsA). This study assessed factors associated with sustained chronic PsA infection and evaluated clinical outcomes after one year of ETI, stratified by PsA status.
Methods
Using the European Cystic Fibrosis Society Patient Registry (ECFSPR), we identified people with cystic fibrosis (pwCF) who initiated ETI between 2019 and 2022. Multivariable logistic regression was used to identify clinical and demographic predictors of persistent chronic PsA. Changes in clinical outcomes from one year before to one year after ETI were analyzed using semiparametric models.
Results
Among 8188 pwCF with chronic PsA prior to ETI, 4908 (59.9 %) remained chronically infected after one year, while 3280 (40.1 %) transitioned to non-chronic PsA. Older age (OR 1.63, 95 %CI: 1.49–1.78) and lower baseline ppFEV₁ (OR 0.64, 95 %CI: 0.58–0.70) were the strongest predictors of persistent chronic PsA. The improvement in ppFEV₁ was similar between those who remained chronic (12.5 %, 95 %CI: 11.8–13.3) and those who shifted to non-chronic status (13.0 %, 95 %CI: 12.2–13.8; p = 0.074). BMI z-score improvements did not differ significantly between groups (p = 0.086). However, the mean hospital admission days was lower in those who shifted to non-chronic PsA (1.2 vs. 1.9 days; p < 0.001).
Conclusion
Risk factors for sustained PsA infection post-ETI are associated with older age and lower ppFEV1. Nonetheless, improvements in lung function and nutritional status were comparable, regardless of PsA status. Further research is required to better understand how PsA affects CF lung disease in the era of ETI treatment.
{"title":"Factors associated with sustained Pseudomonas aeruginosa infection following elexacaftor/tezacaftor/ivacaftor treatment: Real-world data from the European cystic fibrosis society patient registry","authors":"Mordechai Pollak , Simone Gambazza , Annalisa Orenti , Dario Prais , Eitan Kerem , Meir Mei-Zahav , ECFSPR Steering Group","doi":"10.1016/j.jcf.2025.08.019","DOIUrl":"10.1016/j.jcf.2025.08.019","url":null,"abstract":"<div><h3>Background</h3><div>Elexacaftor/tezacaftor/ivacaftor (ETI) therapy reduces airway infection rates with Pseudomonas aeruginosa (PsA). This study assessed factors associated with sustained chronic PsA infection and evaluated clinical outcomes after one year of ETI, stratified by PsA status.</div></div><div><h3>Methods</h3><div>Using the European Cystic Fibrosis Society Patient Registry (ECFSPR), we identified people with cystic fibrosis (pwCF) who initiated ETI between 2019 and 2022. Multivariable logistic regression was used to identify clinical and demographic predictors of persistent chronic PsA. Changes in clinical outcomes from one year before to one year after ETI were analyzed using semiparametric models.</div></div><div><h3>Results</h3><div>Among 8188 pwCF with chronic PsA prior to ETI, 4908 (59.9 %) remained chronically infected after one year, while 3280 (40.1 %) transitioned to non-chronic PsA. Older age (OR 1.63, 95 %CI: 1.49–1.78) and lower baseline ppFEV₁ (OR 0.64, 95 %CI: 0.58–0.70) were the strongest predictors of persistent chronic PsA. The improvement in ppFEV₁ was similar between those who remained chronic (12.5 %, 95 %CI: 11.8–13.3) and those who shifted to non-chronic status (13.0 %, 95 %CI: 12.2–13.8; <em>p</em> = 0.074). BMI z-score improvements did not differ significantly between groups (<em>p</em> = 0.086). However, the mean hospital admission days was lower in those who shifted to non-chronic PsA (1.2 vs. 1.9 days; <em>p</em> < 0.001).</div></div><div><h3>Conclusion</h3><div>Risk factors for sustained PsA infection post-ETI are associated with older age and lower ppFEV<sub>1</sub>. Nonetheless, improvements in lung function and nutritional status were comparable, regardless of PsA status. Further research is required to better understand how PsA affects CF lung disease in the era of ETI treatment.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1098-1104"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The Elexacaftor/Tezacaftor/Ivacaftor (ETI) combination of cystic fibrosis transmembrane regulator modulators is safe and effective even in children with at least one F508del variant. However, cases of liver damage have been reported, and we observed an increase of serum bilirubin and alanine aminotransferase (ALT) in Cystic Fibrosis (CF) adults homozygous or compound heterozygous for the F508del after one year of ETI treatment. In the present study we followed 106 people with CF (pwCF) aged 8–15 years, who were homozygous or compound heterozygous for the F508del variant and treated with ETI, monitoring liver biochemical indices, lipid profile, and circulating cells. Treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s in both pwCF homozygous and compound heterozygous for the F508del variant (p < 0.001). On the other hand, ETI treatment caused a significant increase in total and conjugated bilirubin in both subgroups (p < 0.001). These changes were mostly found after six months of therapy but not continued after one and two years. Furthermore, we observed a significant reduction in the number of blood platelets after ETI treatment. These data suggest to further investigate the effects of ETI therapy on bilirubin metabolism and to search for biomarkers that can predict its increase, whereas we hypothesize that the reduction in platelet count may depend on the reduced systemic inflammation due to ETI treatment.
{"title":"The treatment with Elexacaftor/Tezacaftor/Ivacaftor significantly increases serum bilirubin and decreases blood platelets in children and adolescents with cystic fibrosis homozygous or double heterozygous for the F508del CFTR variant","authors":"Alice Castaldo , Chiara Cimbalo , Cristina Fevola , Valeria Raia , Vito Terlizzi , Monica Gelzo , Angela Sepe , Antonella Tosco","doi":"10.1016/j.jcf.2025.10.001","DOIUrl":"10.1016/j.jcf.2025.10.001","url":null,"abstract":"<div><div>The Elexacaftor/Tezacaftor/Ivacaftor (ETI) combination of cystic fibrosis transmembrane regulator modulators is safe and effective even in children with at least one F508del variant. However, cases of liver damage have been reported, and we observed an increase of serum bilirubin and alanine aminotransferase (ALT) in Cystic Fibrosis (CF) adults homozygous or compound heterozygous for the F508del after one year of ETI treatment. In the present study we followed 106 people with CF (pwCF) aged 8–15 years, who were homozygous or compound heterozygous for the F508del variant and treated with ETI, monitoring liver biochemical indices, lipid profile, and circulating cells. Treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s in both pwCF homozygous and compound heterozygous for the F508del variant (<em>p</em> < 0.001). On the other hand, ETI treatment caused a significant increase in total and conjugated bilirubin in both subgroups (<em>p</em> < 0.001). These changes were mostly found after six months of therapy but not continued after one and two years. Furthermore, we observed a significant reduction in the number of blood platelets after ETI treatment. These data suggest to further investigate the effects of ETI therapy on bilirubin metabolism and to search for biomarkers that can predict its increase, whereas we hypothesize that the reduction in platelet count may depend on the reduced systemic inflammation due to ETI treatment.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1149-1155"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.10.009
Raksha Jain
{"title":"Moving personalized medicine from treatment to prevention – a paradigm shift in genetic conditions","authors":"Raksha Jain","doi":"10.1016/j.jcf.2025.10.009","DOIUrl":"10.1016/j.jcf.2025.10.009","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1015-1016"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145512950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.07.015
Sylvia Szentpetery , Dara Riva , Yair J. Blumenfeld , John F. Engelhardt , Carmen Luna-Paredes , Carlos Milla , Elena K. Schneider-Futschik , Jeanne S Sheffield , Rebecca Darrah , Jane C. Davies , Patrick A Flume , Kimberly E Foil , Christopher N. Fortner , Jennifer S. Guimbellot , Anne D. Lyerly , Nicole Mayer-Hamblett , Clement L. Ren , Jacquelyn Spano , Emma M. Tillman , Aaron Trimble , Jennifer L. Taylor-Cousar
Background
Data from cystic fibrosis (CF) animal models and case studies suggests that in utero administration of CF transmembrane conductance regulator (CFTR) modulators (variant specific therapies, VST) can rescue CFTR-related pathophysiology in the fetus. Use of VST during pregnancy to prevent disease in infants has not been systematically studied. Through stakeholder engagement, we sought to determine if formal research evaluation is warranted.
Methods
We surveyed CF care center directors to assess their awareness of the potential off-label use of VST for in utero treatment of a fetus with CF. We then conducted a one-day, international multidisciplinary workshop to review available pre-clinical and clinical data, embryology principles and federal drug regulation considerations, identify knowledge gaps, and consider future clinical study designs.
Results
Sixty-two unique individuals responded to the survey; 92% were aware of use of VST to treat pregnant females who are CF carriers for the prevention of CF complications in the fetus. Expert workshop presentations suggested that use of VST in pregnant females carrying a fetus with CF to mitigate complications of CF is relatively safe and effective in animal models and human case series to date. Further research is needed to understand the optimal timing of VST initiation during pregnancy to improve clinical outcomes, to understand VST pharmacokinetics, and optimize dosing of VST during pregnancy and lactation, and to evaluate the long-term infant safety among those exposed to VST in utero.
Conclusions
Based on available data and knowledge gaps, stakeholders agreed that formal evaluation of in utero and early life VST therapy in a prospective trial is warranted.
{"title":"PRenatal mOdulator treatment to PrEvent CF complicaTions (PROTECT) workshop report","authors":"Sylvia Szentpetery , Dara Riva , Yair J. Blumenfeld , John F. Engelhardt , Carmen Luna-Paredes , Carlos Milla , Elena K. Schneider-Futschik , Jeanne S Sheffield , Rebecca Darrah , Jane C. Davies , Patrick A Flume , Kimberly E Foil , Christopher N. Fortner , Jennifer S. Guimbellot , Anne D. Lyerly , Nicole Mayer-Hamblett , Clement L. Ren , Jacquelyn Spano , Emma M. Tillman , Aaron Trimble , Jennifer L. Taylor-Cousar","doi":"10.1016/j.jcf.2025.07.015","DOIUrl":"10.1016/j.jcf.2025.07.015","url":null,"abstract":"<div><h3>Background</h3><div>Data from cystic fibrosis (CF) animal models and case studies suggests that <em>in utero</em> administration of CF transmembrane conductance regulator (CFTR) modulators (variant specific therapies, VST) can rescue CFTR-related pathophysiology in the fetus. Use of VST during pregnancy to prevent disease in infants has not been systematically studied. Through stakeholder engagement, we sought to determine if formal research evaluation is warranted.</div></div><div><h3>Methods</h3><div>We surveyed CF care center directors to assess their awareness of the potential off-label use of VST for <em>in utero</em> treatment of a fetus with CF. We then conducted a one-day, international multidisciplinary workshop to review available pre-clinical and clinical data, embryology principles and federal drug regulation considerations, identify knowledge gaps<em>,</em> and consider future clinical study designs<em>.</em></div></div><div><h3>Results</h3><div>Sixty-two unique individuals responded to the survey; 92% were aware of use of VST to treat pregnant females who are CF carriers for the prevention of CF complications in the fetus. Expert workshop presentations suggested that use of VST in pregnant females carrying a fetus with CF to mitigate complications of CF is relatively safe and effective in animal models and human case series to date. Further research is needed to understand the optimal timing of VST initiation during pregnancy to improve clinical outcomes, to understand VST pharmacokinetics, and optimize dosing of VST during pregnancy and lactation, and to evaluate the long-term infant safety among those exposed to VST <em>in utero</em>.</div></div><div><h3>Conclusions</h3><div>Based on available data and knowledge gaps, stakeholders agreed that formal evaluation of <em>in utero</em> and early life VST therapy in a prospective trial is warranted.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1058-1066"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.08.004
J. Wynn , S. Rego , D. Chandler-Brown , R. Carter , A. Talati , M. Zaretsky , A. Trimble
Recent improvements in cell-free DNA technology have enabled non-invasive prenatal testing (NIPT) to screen for fetal single-gene autosomal recessive conditions from maternal blood as early as the first trimester. This technique can determine the fetal risk for cystic fibrosis (CF) with a single blood sample from a pregnant person without the need for a partner sample, which is required for traditional carrier screening.
A retrospective review of 100,106 consecutive general-risk pregnant patients who underwent CF carrier screening was completed. All positive CF carriers underwent cell-free DNA testing, which reported a risk of the fetus being affected with CF. Pregnancies with at least a 1 in 4 risk were classified as high risk. Results of confirmatory testing were solicited from all high-risk cases, and a random sample of 50 % of low-risk cases were used to compute test performance analytics.
The study cohort included 2,587 CF carriers and 20 cases with high-risk cell-free DNA results where the CF-affected status of the fetus/neonate was known, of which 13 were affected. All cases (n = 8) with a 9 in 10 cell-free DNA estimated risk were affected. The assay correctly identified all known affected fetuses as high risk (sensitivity of 100 %). Of the 13 affected, 12 cases had at least one CFTR variant eligible for CFTR modulator therapy. Additionally, 75 % of all cell-free DNA fetal risk results were returned before 18.5 weeks gestation, providing ample time for diagnostic testing and initiation of in utero treatment if indicated.
Carrier screening with reflex to cell-free DNA analysis provides a personalized fetal risk assessment and efficient turnaround times at an early gestational age, without the need for a partner sample for a general risk population. This screening method can precisely guide prenatal diagnostic testing to identify CF-affected fetuses that may benefit from in utero therapy.
{"title":"Routine cell-free DNA prenatal screening identifies pregnancies at high risk for cystic fibrosis that may benefit from fetal therapy","authors":"J. Wynn , S. Rego , D. Chandler-Brown , R. Carter , A. Talati , M. Zaretsky , A. Trimble","doi":"10.1016/j.jcf.2025.08.004","DOIUrl":"10.1016/j.jcf.2025.08.004","url":null,"abstract":"<div><div>Recent improvements in cell-free DNA technology have enabled non-invasive prenatal testing (NIPT) to screen for fetal single-gene autosomal recessive conditions from maternal blood as early as the first trimester. This technique can determine the fetal risk for cystic fibrosis (CF) with a single blood sample from a pregnant person without the need for a partner sample, which is required for traditional carrier screening.</div><div>A retrospective review of 100,106 consecutive general-risk pregnant patients who underwent CF carrier screening was completed. All positive CF carriers underwent cell-free DNA testing, which reported a risk of the fetus being affected with CF. Pregnancies with at least a 1 in 4 risk were classified as high risk. Results of confirmatory testing were solicited from all high-risk cases, and a random sample of 50 % of low-risk cases were used to compute test performance analytics.</div><div>The study cohort included 2,587 CF carriers and 20 cases with high-risk cell-free DNA results where the CF-affected status of the fetus/neonate was known, of which 13 were affected. All cases (<em>n</em> = 8) with a 9 in 10 cell-free DNA estimated risk were affected. The assay correctly identified all known affected fetuses as high risk (sensitivity of 100 %). Of the 13 affected, 12 cases had at least one <em>CFTR</em> variant eligible for CFTR modulator therapy. Additionally, 75 % of all cell-free DNA fetal risk results were returned before 18.5 weeks gestation, providing ample time for diagnostic testing and initiation of <em>in utero</em> treatment if indicated.</div><div>Carrier screening with reflex to cell-free DNA analysis provides a personalized fetal risk assessment and efficient turnaround times at an early gestational age, without the need for a partner sample for a general risk population. This screening method can precisely guide prenatal diagnostic testing to identify CF-affected fetuses that may benefit from <em>in utero</em> therapy.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1067-1072"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.10.012
Edith T. Zemanick , Manesha Putra , Hannah Elfman , Michael V. Zaretsky , Jordana E. Hoppe
{"title":"Letter to the editor: False reassurance following single gene non-invasive prenatal testing for cystic fibrosis","authors":"Edith T. Zemanick , Manesha Putra , Hannah Elfman , Michael V. Zaretsky , Jordana E. Hoppe","doi":"10.1016/j.jcf.2025.10.012","DOIUrl":"10.1016/j.jcf.2025.10.012","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1189-1190"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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